Arrhythmias are caused by abnormalities in the cell membrane where electrical signalling is generated. Alterations in normal signal generation or propagation lead to disordered cardiac electrical activity, that is, arrhythmias, which can severally and lethally compromise the cardiac function of pumping oxygenated blood. Arrhythmias following myocardial infarction have become a significant public health problem. For example, following occlusion of a coronary artery, arrhythmias develop due to the ensuing ischemia and infarction. Further, following an acute period of approximately one hour, there is a second risk period which generally occurs between 18 and 72 hours, referred to as the delayed phase, during which arrhythmias, predominantly ventricular tachycardia, (i.e. rapid rhythms) occur.
The primary research approach to studying arrhythmias is by use of animal models, of which the canine is the most important. The major animal model for studying these arrhythmias is the Harris 24 hour dog infarct model, typically generated by a two stage ligation of the left anterior descending (LAD) coronary artery. A surgical ligature around this major artery, which normally provides blood for a portion of the left ventricle, acts to induce a myocardial infarction, thus simulating a "heart attack". This model is studied at 24 hours after the coronary artery ligation, at which time ventricular arrhythmias are generally seen. The locus of origin of these arrhythmias in the experimental model is the subendocardial Purkinje cell layer over the infarct (generally the apical region of the left ventricle). These Purkinje cells survive, but have depolarized membrane potentials and rapid abnormal spontaneous activity. The rapid abnormal spontaneous activity generated in these abnormal cells subsequently spreads throughout the ventricle, and, as a result, interferes with normal conduction patterns and potentially reduces cardiac output.
Elevations of intracellular sodium activity long have been known to cause so called "triggered" arrhythmias through a slightly different cellular process than the abnormal spontaneous activity referred to above (e.g. "abnormal automaticity"). We had previously measured the intracellular sodium ion activity in Purkinje fibers from 24 hour infarcts and discovered that it was elevated by more than 50%. It is believed that this increase may contribute an additional mechanism for the arrhythmias seen in this experimental model.
Antiarrhythmic therapies in the past have concentrated on drugs which block various ion channels, such as calcium channel blockers, or in some cases hormonal membrane receptors, such as beta blockers. Antiarrhythmic drugs generally are designed to bind to receptors in the cardiac membrane, some of which are themselves ion channel proteins, and in binding to normalize or otherwise ameliorate the disordered electrical activity. There are inherent disadvantages associated with these therapies. A particular severe drawback is that sufficiently high doses of these antiarrhythmic drugs needed to suppress the arrhythmias can result in deleterious side effects, including causing other, possibly more severe, arrhythmias. For example, the class I sodium channel blocker type anti-arrhythmic drugs can potential reentrant arrhythmias and central nervous system pathology, while the class II calcium channel blocker type anti-arrhythmic or beta blocker type drugs can reduce cardiac output causing additional cardiac or systemic ischemia.
An additional therapy involves the use of zatebradine. Zatebradine is a benzazepine derivative, as disclosed in U.S. Pat. No 4,490,369 to Reiffen et al. Reiffen et al. found that these derivatives exhibit useful pharmocodyanmic properties, including mild hypotensive activity and selective bradycardiac activity. Vos et al. proposed the use of zatebradine in a different animal model of 24 hour arrhythmias, specifically, the Harris dog with surgical AV block (Vos, M A, Leunissen, J D, van der Zande, J, Wellens, H J (1994) "UL-FS 49, a rather selective blocker of the pacemaker current I.sub.f has no effect on automatic ventricular arrhythmias occurring 24 hours after infarction," Journal of American College of Cardiology, 23:183a). However, Vos et al. did not appreciate that normal sinoatrial conduction was required for zatebradine to slow arrhythmias. Surgical AV block prevents normal or paced sinoatrial conduction. Additionally, the use of zatebradine for the treatment of high blood pressure and cardiac insufficiency is taught in European patent application EP-A 88-11-7181.
A need still exists for an anti-arrhythmic therapy which slows ventricular rhythms without producing deleterious side effects. It is believed that the use of the drug zatebradine, coupled with careful atrial pacing, not only slows ventricular rhythms, but does not result in the side effects experienced with prior art therapies.